Biomedical subjects

J Logan

Publications and source records attributed to J Logan.

At least 145 records · Page 8Linked to original sources

PubMed1993

Effects of central cholinergic blockade on striatal dopamine release measured with positron emission tomography in normal human subjects.

Previously we demonstrated that positron emission tomography (PET) can be used to measure changes in the concentrations of synaptic dopamine and acetylcholine. Whether induced directly or indirectly through interactions with other neurotransmitters, these studies support the use of PET for investigating the functional responsiveness of a specific neurotransmitter to a pharmacologic challenge. In an extension of these findings to the human brain, PET studies designed to measure the responsiveness of striatal dopamine release to central cholinergic blockade were conducted in normal male volunteers using high-resolution PET and [11C]raclopride, a D2-dopamine receptor antagonist. [11C]Raclopride scans were performed prior to and 30 min after systemic administration of the potent muscarinic cholinergic antagonist, scopolamine (0.007 mg/kg). After scopolamine administration, [11C]raclopride binding decreased in the striatum (specific binding) but not in the cerebellum (nonspecific binding) resulting in a significant decrease, exceeding the test/retest variability of this ligand (5%), in the ratio of the distribution volumes of the striatum to the cerebellum (17%). Furthermore, scopolamine administration did not alter the systemic rate of [11C]raclopride metabolism or the metabolite-corrected plasma input function. These results are consistent not only with the known inhibitory influence that acetylcholine exerts on striatal dopamine release but also with our initial 18F-labeled N-methylspiroperidol and benztropine studies. Thus these data support the use of PET for measuring the functional responsiveness of an endogenous neurotransmitter to an indirect pharmacologic challenge in the living human brain.

Adult↗

PubMed1993

Striatal binding of the PET ligand 11C-raclopride is altered by drugs that modify synaptic dopamine levels.

Bilateral decreases in striatal 11C-raclopride binding were observed in adult female baboons with high resolution PET following administration of drugs that act centrally on dopaminergic neurons. At baseline and following administration of d-amphetamine (a dopamine-releasing drug), GBR-12909 (a potent dopamine reuptake inhibitor), or tetrabenazine (a biogenic amine depleting drug) PET scans of 11C-raclopride binding were obtained in a CTI 931 positron tomograph. In all studies, the ratio of the distribution volumes for the striatum to the cerebellum for 11C-raclopride binding decreased significantly by an average of 16.2% for d-amphetamine, 22.1% for GBR-12909, and 28.3% for tetrabenazine while there were no significant changes observed in the cerebellum or in the rate of systemic metabolism of the radiotracer. These decreases exceed the test/retest variability of striatal 11C-raclopride binding measured in the same animals under identical experimental conditions (Dewey et al., 1992b). Together these studies demonstrate that PET measurements of striatal 11C-raclopride binding can be used to indirectly and non-invasively monitor changes in synaptic dopamine concentrations that result from a variety of neurophysiologic mechanisms.

Animals↗

PubMed1993

Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers.

Decreased dopaminergic function has been postulated to underlie cocaine addiction. To examine the possibility that dysfunction of brain regions subserved by the dopamine system could promote cocaine self-administration, positron emission tomography and a dual-tracer approach was used to examine dopamine D2 receptor availability and regional brain glucose metabolism in cocaine abusers. When compared to normal controls, cocaine abusers showed significant decreases in dopamine D2 receptor availability which persisted 3-4 months after detoxification. Decreases in dopamine D2 receptor availability were associated with decreased metabolism in several regions of the frontal lobes, most markedly orbito-frontal cortex and cingulate gyri. Dopamine dysregulation of these brain areas which are involved in the channeling of drive and affect could lead to loss of control resulting in compulsive drug-taking behavior.

Adult↗

PubMed1993

One-step affinity isolation of recombinant protein using the baculovirus/insect cell expression system.

We have developed two baculovirus transfer vectors which allow single-step affinity isolation of recombinant proteins after expression in insect cells. Using these vectors, recombinant proteins are synthesized as fusions with glutathione-S-transferase and are amenable to enrichment from a crude insect cell lysate using glutathione affinity agarose. After affinity isolation, glutathione-S-transferase can be cleaved from the recombinant polypeptides of interest at an engineered thrombin cleavage site. We used this approach to successfully isolate glutathione-S-transferase, the human low density lipoprotein receptor, two large polypeptides containing cytoplasmic domains of the cystic fibrosis transmembrane conductance regulator (CFTR), and the full-length CFTR. The approach has potential advantages over prokaryotic overexpression of foreign polypeptides, including: (i) eukaryotic post-translational modification of expressed protein, (ii) increased solubility of recombinant fusion proteins synthesized in insect cells leading to increased affinity yield under mild conditions, and (iii) production of large and/or complex polypeptides which might be difficult to purify from prokaryotic cells. The method also allows enrichment of recombinant protein representing a small fraction (less than 5%) of total insect cell protein produced and provides a general method for eukaryotic protein synthesis and isolation which is independent of the particular protein being expressed.

Animals↗

PubMed1993

Modulation of central cholinergic activity by GABA and serotonin: PET studies with 11C-benztropine in primates.

The pharmacologic treatment of many neuropsychiatric disorders (Alzheimer's disease, schizophrenia, depressive illness) has been targeted at the central hypothesis that defects in a single neurotransmitter system underlie the pathophysiology of the disease state. With the recognition that such treatments have not been efficacious consistently, recent drug development has been directed at altering other functionally linked neurotransmitters involved in these diseases. Using positron emission tomography, we have noninvasively investigated the effects of two noncholinergic drugs on the release of acetylcholine. By examining the effects of gamma-vinyl gamma-aminobutyric acid (GABA) (a GABA transaminase inhibitor) or altanserin (a serotonergic antagonist) on the regional binding of 11C-benztropine in the primate brain (Papio anubis), we demonstrated that drugs acting upon either GABAergic or serotonergic neurons produce profound regional changes in acetylcholine release. These findings indicate that the mechanisms of action and the subsequent therapeutic efficacy of these centrally acting drugs may be linked to their multitransmitter effects. This application of positron emission tomography represents an extremely promising experimental approach that can be directed towards elucidating abnormalities in neurotransmitter modulation relevant to disease progression and pharmacologic treatment.

4-Aminobutyrate Transaminase↗

PubMed1993

Monoamine oxidase B (MAO B) inhibitor therapy in Parkinson's disease: the degree and reversibility of human brain MAO B inhibition by Ro 19 6327.

The possibility of slowing the progression of Parkinson's disease (PD) with inhibitors of monoamine oxidase B (MAO B) has stimulated the development of new MAO B inhibitor drugs. Ro 19 6327 is a highly selective inhibitor of MAO B currently under clinical investigation. We used positron emission tomography (PET) and the MAO B tracer [11C]L-deprenyl to determine the degree and reversibility of human brain MAO B inhibition by Ro 19 6327 in six early Parkinson's disease patients who were treated with different doses of Ro 19 6327 (25 mg [n = 3], 50 mg [n = 2], and 100 mg [n = 1]; 0.34 to 1.4 mg/kg) every 12 hours for 1 week. Each patient had three PET scans to assess baseline MAO B activity, degree of trough inhibition, and reversibility. A control group of four elderly normal subjects was scanned twice to assess reproducibility of repeated measures. Four of the patients showed reduction of MAO B concentration to 1% to 7% of baseline on doses of 0.43 mg/kg or greater, and the remaining two at 0.34 mg/kg showed significant but incomplete inhibition (10% to 21% of baseline in the global region and in the thalamus, basal ganglia, and mesencephalon). Thus, 0.4 mg/kg or greater of Ro 19 6327 given every 12 hours is the minimum dose necessary to provide > 90% inhibition of brain MAO B in patients with early PD. Brain MAO B activity returned to baseline values by 36 hours after drug discontinuation.

Aged↗

PubMed1993

Synthesis and PET studies of fluorine-18-BMY 14802: a potential antipsychotic drug.

BMY 14802 is a compound containing fluorine developed as a potential antipsychotic drug. It has a moderate affinity for the sigma binding site and a very low affinity for dopamine D2 receptors and has been predicted to have antipsychotic properties without the side effect potential of existing drugs. To assess the brain uptake, pharmacokinetics, stereoselectivity and binding properties of this potential antipsychotic drug, enantiomerically pure samples of (-) and (+)-[18F]BMY 14802 were examined in a baboon with PET. A tissue distribution with racemic labeled BMY 14802 was also carried out in mice. Radiochemical yields of 15% at the end of bombardment (EOB) for the racemic mixture, and 5% for each enantiomer with a specific activity of 2-5 Ci/mumol at EOB were obtained. In baboons, [18F]BMY 14802 cleared rapidly from the plasma and the glucuronidated [18F]BMY 14802 appeared. Radioactivity peaked (0.04-0.07% dose/cc) in all areas of the brain examined at about 5 min postinjection. It then rapidly cleared to about 30% of peak value by 20 min postinjection and to less than 10% of peak by 60 min postinjection in all regions. A similar rapid clearance from brain was also observed in mice. Pretreatment with unlabeled BMY 14802 (7 mg/kg), did not produce the expected reductions in distribution volume and clearance halftimes consistent with receptor binding. Although the rapid kinetics of [18F]BMY 14802 made it difficult to resolve the processes of transport and binding of the labeled drug, the lack of regional distribution consistent with the known distribution of sigma binding sites as well as the lack of stereoselectivity suggest that the behavior of BMY 14802 in the brain is dominated by its transport properties in tissue rather than its binding to sigma sites. Moreover, its rapid clearance from brain may be a limiting factor in its use as an antipsychotic drug.

Animals↗

PubMed1993

Reproducibility of repeated measures of carbon-11-raclopride binding in the human brain.

Carbon-11-raclopride has been successfully utilized with PET to assess changes in endogenous dopamine concentration after pharmacological intervention in the living baboon brain. For similar studies to be done in humans, measurements of 11C-raclopride with no intervention need to be reproducible. In order to test the reproducibility (test-retest) of 11C-raclopride binding in the human brain, we performed repeated studies on two different days. Studies were done in five normal controls with no pharmacological intervention. Time-activity (%dose/cc) curves for 11C-raclopride in the basal ganglia (BG) and cerebellum (CBL) were highly reproducible with an average difference in peak uptake for repeated studies in the same individual of 4%. The BG to CBL ratio for the average activity concentration between 30 and 60 min showed differences that ranged from -7% to 8% between the repeated studies. Graphical analysis to obtain the distribution volume revealed intrasubject values that ranged from -9% to 7% for the ratio of the distribution volume in BG to that in CBL. These studies demonstrate that in order to use 11C-raclopride to measure an individual's change in relative dopamine concentration secondary to pharmacological or behavioral intervention, a change in striatal 11C-raclopride binding in excess of 10% is required.

Adult↗

PubMed1993

Comparison of high specific activity (-) and (+)-6-[18F]fluoronorepinephrine and 6-[18F]fluorodopamine in baboons: heart uptake, metabolism and the effect of desipramine.

(-)-Norepinephrine is the principal neurotransmitter of the mammalian sympathetic nervous system and a major CNS neurotransmitter. The simple ring fluorinated derivatives of (-)- and (+)-norepinephrine [(-)- and (+)6-fluoronorepinephrine] and dopamine (6-fluorodopamine) have been labeled with 18F in high specific activity (2-5 Ci/mumol) and evaluated as tracers for (-)-norepinephrine. Comparative PET studies of (-) and (+)-6-[18F]fluoronorepinephrine [(-)-6-[18F]FNE and (+)-6-[18F]FNE] and 6-[18F]fluorodopamine (6-[18F]FDA) in the same baboon showed strikingly different kinetics in the heart. Analysis of plasma showed more rapid metabolism of 6-[18F]FDA with only 1%-2% of 18F remaining as parent tracer at 10 min after injection of 6-[18F]FDA, in contrast to 28% and 17% remaining after injection of (-) and (+)-6-[18F]FNE. No changes in vital signs were observed at any time during the study. Pretreatment with desipramine (0.5 mg/kg), a tricyclic antidepressant drug which interacts with a binding site associated with norepinephrine reuptake, markedly decreased cardiac uptake of 6-[18F]FDA and (-)-6-[18F]FNE. However, a greater blocking effect was observed for (-)-6-[18F]FNE. These studies show that (-) and (+)-6-[18F]FNE are similar to (-)- and (+)-norepinephrine in their patterns of metabolism and clearance in the heart and that (-)-6-[18F]FNE is a promising tracer for endogenous (-)-norepinephrine.

Animals↗

PubMed1993

Nurses' learning patterns.

Staff nurses are expected by nurse administrators and educators to incorporate nursing theory, diagnosis and researched-based interventions into highly technical patient care. However, there has been minimal systematic observation of how nurses learn in clinical practice and how that learning could be enhanced. Recently, an exploratory study was conducted to start filling that gap.

Clinical Competence↗

PubMed1992

Regional distribution and kinetics of haloperidol binding in human brain: a PET study with [18F]haloperidol.

The regional distribution and the kinetics of haloperidol uptake in human brain were examined using [18F]haloperidol and PET in 9 controls and 5 schizophrenics while on haloperidol medication and after haloperidol washout. The regional distribution of [18F]N-methylspiroperidol, a tracer for D2 receptors, was measured in 1 normal subject for comparison. The uptake of [18F]haloperidol in the whole brain in normals was high (6.6% of the injected dose at 2 hr), and regional distribution was much more extensive than could be accounted for by the distribution of dopamine D2 receptors. In normals, the cerebellum, basal ganglia, and thalamus showed a greater concentration than the cortex, and there was minimal clearance of 18F from the brain during the 10-hr period of the study. Medicated schizophrenics showed a total brain uptake of 4.0% and had a significant clearance of [18F]haloperidol from brain and a higher concentration of [18F]haloperidol in plasma. After withdrawal from medication, [18F]haloperidol clearance from brain became slower than while on medication. These results are discussed in terms of the pharmacokinetics of haloperidol in the human brain and its binding to dopamine D2 receptors and to sigma receptors.

Adult↗

PubMed1992

Comparative PET studies of the kinetics and distribution of cocaine and cocaethylene in baboon brain.

Recent studies have suggested that cocaethylene, an active metabolite of cocaine found in blood and postmortem brain of individuals self-administering cocaine and alcohol, may play a role in the increased toxicity seen when coadministering these 2 drugs. We have used positron emission tomography (PET) and carbon-11 (t1/2:20.4 min) labeled cocaine and cocaethylene to compare the short-term kinetics of cocaine and cocaethylene in baboon brain. The regional uptake of [11C]cocaine cocaethylene in baboon brain. The regional uptake of [11C]cocaine ([11C]COC) and [11C]cocaethylene ([11C]CE), 5-8 mCi and 4-6 micrograms, in baboon brain (n = 7) were similar but clearance from whole brain (global, GL) and from striatum (SR), thalamus (TH), and cerebellum (CB) was slower for cocaethylene. Steady-state distribution volumes (DV) were not significantly different in the striatum but were greater for cocaethylene in the thalamus, cerebellum, and whole brain. Debenzoylation of cocaethylene proceeded at about one-third the rate of cocaine, as determined by in vitro incubation of labeled cocaethylene and labeled cocaine with baboon plasma and with purified horse butyryl-cholinesterase (EC 3.1.1.8). Even though the slower clearance of cocaethylene could lead to longer tissue exposures and potentially accentuated or different physiological effects relative to cocaine, the difference between the 2 drugs is not large. Thus it is more likely that the direct actions of cocaine and alcohol on some organs, rather than cocaethylene, account for this enhanced toxicity.

Animals↗

PubMed1992

Alcohol intoxication does not change [11C]cocaine pharmacokinetics in human brain and heart.

There is increasing evidence that the combined use of cocaine and alcohol produces enhanced behavioral and toxic effects. We have used PET and tracer doses of [11C]cocaine in 7 normal human volunteers to assess if the distribution and clearance of cocaine are altered by alcohol intoxication. Each subject received 2 PET studies with [11C]cocaine (3-11 micrograms), one before and one during alcohol intoxication (1 g/kg). Regions of interest included the brain (n = 3) and heart (n = 4). Arterial plasma was assayed for unchanged cocaine and for labeled cocaethylene, a metabolite of cocaine found in individuals using cocaine and alcohol in combination (Hearn et al., 1991a). Alcohol intoxication did not change uptake and clearance or the steady-state distribution volume of [11C] cocaine in brain (striatum, thalamus, and cerebellum) or in heart. Moreover, labeled cocaethylene was not detected in the 10 minute plasma sample. These results suggest that the acute enhancement of behavior and toxicity associated with the combined use of cocaine and alcohol is not due to an alteration in cocaine's organ distribution or to cocaethylene formation but may be related to an additive effect resulting from the direct actions of each of these drugs.

Adult↗

PubMed1992

Knowing the patient: one aspect of clinical knowledge.

This paper analyzes the concept "knowing the patient" which was identified in a qualitative study of expert nursing practice during ventilator weaning of adult patients. The concept signified a cognitive and relational process by which the study participants determined salient aspects of a particular patient situation, while at the same time demonstrating their credibility and eliciting patient trust. The paper describes the clinical judgments, decisions, actions and patient outcomes that ensue from knowing the patient. This analysis offers a contextually specific description of nurses' clinical reasoning that illustrates a dimension of expert clinical practice from actual rather than simulated clinical content.

Cognition↗

PubMed1992

GABAergic inhibition of endogenous dopamine release measured in vivo with 11C-raclopride and positron emission tomography.

Extensive neuroanatomical, neurophysiological, and behavioral evidence demonstrates that GABAergic neurons inhibit endogenous dopamine release in the mammalian corpus striatum. Positron emission tomography (PET) studies in adult female baboons, using the dopamine D2-specific radiotracer 11C-raclopride, were undertaken to assess the utility of this imaging technique for measuring these dynamic interactions in vivo. 11C-raclopride binding was imaged prior to and following the administration of either gamma-vinyl-GABA (GVG), a specific suicide inhibitor of the GABA-catabolizing enzyme GABA transaminase, or lorazepam, a clinically prescribed benzodiazepine agonist. Striatal 11C-raclopride binding increased following both GVG and lorazepam administration. This increase exceeded the test/retest variability of 11C-raclopride binding observed in the same animals. These findings confirm that changes in endogenous dopamine concentrations resulting from drug-induced potentiation of GABAergic transmission can be measured with PET and 11C-raclopride. Finally, this new strategy for noninvasively evaluating the functional integrity of neurophysiologically linked transmitter systems with PET supports its use as an approach for assessing the multiple mechanisms of drug action and their consequences in the human brain.

Aminocaproates↗

PubMed1992

Distribution and kinetics of carbon-11-cocaine in the human body measured with PET.

The extent to which the toxic properties of cocaine are related to its accumulation in various organs is not known. This study investigates cocaine uptake in the human body using 11C-cocaine and PET in 14 healthy males. The rate of uptake and clearance of 11C-cocaine varied among organs: peak uptake occurred in the lungs at 45 sec, in the heart and kidneys at 2-3 min, in the adrenals at 7-9 min, and in the liver at 10-15 min. Half-peak clearances were 90 sec in the lungs, 10 min in the heart and kidneys and 22 min in the adrenals. Liver radioactivity plateaued 10-15 min after injection and remained constant thereafter (40 min). Lung radioactivity paralleled that of plasma. The average uptake at peak was 0.007% (s.d., 0.001) dose/cc in the heart, 0.014% (s.d., 0.002) dose/cc in the kidney, 0.014% (s.d., 0.002) dose/cc in the liver and 0.034% (s.d., 0.001) dose/cc in the adrenals. The significant accumulation of cocaine in human heart, kidneys, adrenals and liver could contribute to its toxicity.

Adult↗

PubMed1992

Is [1-11C]putrescine useful as a brain tumor marker?

Our experience with 11C-putrescine underscores the difficulty of finding a selective brain tumor tracer, uniquely incorporated by neoplastic glia or metastatic cells within brain, but not by the proliferating, nontransformed cells which constitute a normal pathophysiological reaction to various disease processes. Thirty-three patients with 36 lesions were studied with 11C-putrescine to determine the specificity of labeled putrescine for tumor tissue. The uptake of 11C-putrescine was correlated with local cerebral glucose metabolic rate in various lesions, including different types of tumors, to assess the relationship between 11C-putrescine uptake and tumor biology. Carbon-11-putrescine uptake was similar in malignant tumor and benign, non-neoplastic lesions with blood-brain barrier breakdown, illustrating the lack of tumor specificity of this tracer. Carbon-11-putrescine was not well incorporated into poorly enhancing lesions, regardless of their pathology, emphasizing the requirement of a disrupted blood-brain barrier for 11C-putrescine uptake. The ratio of 11C concentration within lesions, compared to that in a region of interest in the contralateral brain, weakly correlated with an analogous ratio for local cerebral glucose metabolic rate in various lesions. Physiological processes not unique to tumors are associated with polyamine active transport and metabolism and contribute to the lack of tumor specificity of 11C-putrescine. Carbon-11-putrescine appear to have less diagnostic utility than 18FDG in brain tumors. The potential of 11C-putrescine for evaluating the effect of antineoplastic therapy and providing prognostic information on brain tumors remains to be investigated.

Biomarkers, Tumor↗

PubMed1991

Use of H2-receptor antagonists in patients with dyspepsia and heartburn: a cost comparison.

OBJECTIVE: Under the Pharmaceutical Benefits Scheme, the use of H2-receptor antagonists (H2A) in the treatment of dyspepsia and heartburn is only subsidised when there is a proven diagnosis of ulcer. This study compared the costs of this Australian practice with a simulation of British practice, which allows unrestricted prescribing of subsidised H2A. DESIGN: Patients with heartburn and/or dyspepsia were prospectively randomised to either a "British" group treated freely at the discretion of their general practitioner without necessarily being investigated or an "Australian" group where use of H2A was allowed only after gastroscopy or a barium meal had demonstrated a peptic ulcer or ulcerative oesophagitis. The patients were followed up for six months and all direct and indirect costs were recorded. SETTING: Forty-nine Sydney general practitioners recruited primary care patients for the study. PATIENTS: Any patient with heartburn or dyspepsia was considered for recruitment; 139 patients entered the study and 137 completed it. MAIN OUTCOME MEASURES: The outcome measures were the costs of general practitioner consultations, specialist consultations, radiology and gastroscopy, other tests, H2A, other medications, personal costs, and total cost per patient. RESULTS: The cumulative total cost per patient at the end of the study was equivalent in the "Australian" ($392) and "British" ($406) groups. A higher initial cost per patient of H2A in the "British" group was offset by a rapid decrease in the proportion that continued to use H2A and by the cost of specialist consultations and investigations in the "Australian" group. CONCLUSION: Over a six-month period the cost of early investigation of heartburn and dyspepsia was equivalent to the cost of a therapeutic trial of H2A.

Adult↗